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Abstract:

Provided is a methylphenidate patch preparation superior in the stability
of a drug (methylphenidate and/or a salt thereof) in the patch
preparation, skin permeability of a drug during use of the patch
preparation, and methylphenidate availability. A patch preparation having
a support and an adhesive layer formed on at least one surface of the
support, wherein the adhesive layer contains methylphenidate and/or a
salt thereof, polyisobutylene and a liquid plasticizer. The liquid
plasticizer preferably has an HLB value of 1.0-3.3.

Claims:

1. A patch preparation comprising a support and an adhesive layer formed
on at least one surface of the support, wherein the adhesive layer
comprises methylphenidate and/or a salt thereof, polyisobutylene and a
liquid plasticizer.

2. The patch preparation according to claim 1, wherein the liquid
plasticizer has an HLB value of 1.0-3.3.

3. The patch preparation according to claim 1, wherein the
polyisobutylene comprises a first polyisobutylene having a viscosity
average molecular weight of 160,000-6,000,000 and a second
polyisobutylene having a viscosity average molecular weight of
30,000-100,000.

4. The patch preparation according to claim 3, wherein the ratio of the
amount of the first polyisobutylene and the amount of the second
polyisobutylene (first polyisobutylene:second polyisobutylene) is
1:0.1-10 in weight ratio.

5. The patch preparation according to claim 1, wherein the adhesive layer
further comprises a tackifier.

Description:

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to a methylphenidate patch
preparation (patch preparation containing methylphenidate and/or a salt
thereof as a drug). More particularly, the present invention relates to a
methylphenidate patch preparation superior in the stability of a drug in
the patch preparation, skin permeability of a drug during use of the
patch preparation, and drug availability.

BACKGROUND OF THE INVENTION

[0002] Attention Deficit Disorder and Attention Deficit Hyperactivity
Disorder are most generally seen in children with mental disorders. The
morbidity rate of Attention Deficit Disorder has been reported to be
4%-9%.

[0003] Attention Deficit Disorder and Attention Deficit Hyperactivity
Disorder are characterized by carelessness and impulsivity, and are often
accompanied by hyperactivity. They may be developed in association with
an emotional disorder, may induce aggression, stealing, lie, truant,
arson, runaway, temper and the like, or may sometimes be accompanied by
decrease in cognitive ability and learning ability and decreased social
skill.

[0004] Methylphenidate is a psychostimulant most often used for the
treatment of Attention Deficit Disorder and Attention Deficit
Hyperactivity Disorder.

[0005] As compared to other psychostimulants, this drug highly frequently
expresses good effects and less frequently expresses a bad influence. The
effect of methylphenidate for the improvement of attention and behavioral
symptoms has been confirmed by many studies.

[0006] However, currently available methylphenidate therapeutic agents
have many problems. For example, "immediate-release tablets" (for oral
administration) of methylphenidate show dispersed blood concentrations of
methylphenidate and short half-life of methylphenidate. To ensure
appropriate treatment during children's school hours, therefore, the
tablets need to be administered frequently at short intervals.

[0007] While sustained-release methylphenidate tablets are also
commercially available, the reported defects thereof include difficulty
in swallowing, insufficient effect of sustained release of
methylphenidate, which prevents an appropriate treatment effect during
children's school hours, and possible drug abuse.

[0008] On the other hand, patch preparation provides many advantages as
compared to oral administration preparations, such as convenient
administration, improved compliance of patients, easy interruption of
administration, absence of first pass effect in the liver, sustained
blood concentration for a long time, improved treatment effect and the
like. Therefore, a patch preparation is considered to be a superior
administration form also for methylphenidate.

[0009] For use as a drug for patch preparation, however, methylphenidate
is known to be unstable and undergoes degradation in the presence of acid
functional groups contained in adhesive, permeation promoter, additive
and other components (patent document 1 and the like). Patent document 1
relates to the stability of methylphenidate in an adhesive layer of a
patch preparation and discloses a methylphenidate-stabilizing effect of a
substituent in an acrylic adhesive. Patent document 1 also discloses a
sustained-release effect of methylphenidate in a patch preparation by a
combination of an acrylic adhesive and a silicone adhesive as an
adhesive.

[0010] Generally, the release rate of a drug from a patch preparation is
slow as compared to that of preparations for oral administration such as
tablet, capsule and the like. Since the release rate is slow, the
treatment effect lasts for a long time. Utilizing such characteristics,
patch preparation is often used as a sustained-release preparation.
However, a patch preparation for transdermal administration of
methylphenidate to treat Attention Deficit Disorder or Attention Deficit
Hyperactivity Disorder needs to show a certain level of rapid release
rate (particularly initial release rate) and superior skin permeability
of methylphenidate, because the treatment effect needs to be provided
within a comparatively short time (children's school hours). To ensure an
appropriate treatment throughout children's school hours, moreover, a
therapeutically effective amount needs to be delivered, and a cumulative
permeation amount of methylphenidate to the skin needs to be appropriate,
i.e., superior drug availability. [0011][patent document 1]U.S. Pat. No.
6,348,211

DISCLOSURE OF THE INVENTION

Problems to be Solved by the Invention

[0012] The present invention was made in view of such situation and aims
to provide a methylphenidate patch preparation, which shows high
stability of a drug (methylphenidate and/or a salt thereof) therein, and
superior skin permeability of the drug during use.

[0013] In addition, the present invention aims to provide a
methylphenidate patch preparation, which shows high stability of a drug
(methylphenidate and/or a salt thereof) therein, superior skin
permeability of the drug during use and superior drug availability.

Means of Solving the Problems

[0014] The present inventors have conducted intensive studies in an
attempt to solve the above-mentioned problems and found that a patch
preparation comprising a support and an adhesive layer formed on at least
one surface of the support, wherein the adhesive layer is a plaster
comprising methylphenidate and/or a salt thereof as a drug,
polyisobutylene as an adhesive, and a liquid plasticizer can afford a
methylphenidate patch preparation, which shows less decrease in the drug
content, superior skin permeability of the drug and superior drug
availability, since methylphenidate and/or a salt thereof are/is
stabilized in the plaster (adhesive layer). In addition, they have found
that the stability of methylphenidate and/or a salt thereof in the patch
preparation can be improved more when the aforementioned liquid
plasticizer has an HLB value, which is an index of
hydrophilicity-lipophilicity balance, of not more than 3.3, which
resulted in the completion of the present invention.

[0015] Accordingly, the present invention relates to

(1) a patch preparation comprising a support and an adhesive layer formed
on at least one surface of the support, wherein the adhesive layer
comprises methylphenidate and/or a salt thereof, polyisobutylene and a
liquid plasticizer, (2) the patch preparation according to (1) above,
wherein the liquid plasticizer has an HLB value of 1.0-3.3, (3) the patch
preparation according to (1) above, wherein the polyisobutylene comprises
a first polyisobutylene having a viscosity average molecular weight of
160,000-6,000,000 and a second polyisobutylene having a viscosity average
molecular weight of 30,000-100,000, (4) the patch preparation according
to (3) above, wherein the ratio of the amount of the first
polyisobutylene and the amount of the second polyisobutylene (first
polyisobutylene:second polyisobutylene) is 1:0.1-10 in weight ratio, and
(5) the patch preparation according to (1) above, wherein the adhesive
layer further comprises a tackifier.

EFFECT OF THE INVENTION

[0016] The present invention can provide a methylphenidate patch
preparation, which can stabilize a drug (methylphenidate and/or a salt
thereof), particularly minimize a decrease in the drug content during
preservation of the preparation, and shows superior skin permeability of
the drug during use and superior drug availability. Therefore, the patch
preparation of the present invention can be preferably used for the
treatment or prophylaxis of Attention Deficit Disorder, Attention Deficit
Hyperactivity Disorder and the like. Particularly, it is effective for
treating children suffering from the aforementioned disorders through
children's school hours and in a comparatively short time, and provides
effects such as a sedating effect, decrease of impulsive behaviors,
enhanced concentration and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

[0017] The present invention is explained in detail in the following. The
content (amount) indicated in wt % unit of each component constituting
the adhesive layer described below shows percentage of the ratio (weight
ratio) of each component relative to the total weight of the entire
components except the solvent used for forming an adhesive layer, namely,
the whole adhesive layer.

[0018] The patch preparation of the present invention has a support, and
an adhesive layer provided on at least one surface of the support, and is
mainly characterized in that the adhesive layer contains methylphenidate
as a drug and/or a salt thereof, polyisobutylene as an adhesive, and a
liquid plasticizer.

[0019] Methylphenidate contains 4 stereoisomers (d-threo, d-erythro,
1-threo and 1-erythro). It preferably contains at least
d-threo-methylphenidate, and dl-threoracemate can be used particularly
preferably.

[0020] In the present invention, examples of the salt of methylphenidate
include pharmaceutically acceptable salts such as hydrochloride,
hydrobromide, sulfate, phosphate, citrate, lactate, ascorbate, acetate,
maleate, tartrate, malate, succinate and the like. In addition, an ester
of acid, for example, quaternary ammonium salt of methylphenidate formed
by reacting ester of hydrohalic acid such as methyl chloride, methyl
bromide, ethyl chloride etc. and the like with methylphenidate can also
be mentioned.

[0021] Methylphenidate and the salt of methylphenidate may be in the form
of solvate such as hydrate and the like. They can be obtained by a known
synthesis means.

[0022] In the patch preparation of the present invention, while the
pharmacological use of methylphenidate and/or a salt thereof (hereinafter
to be also referred to as "methylphenidate etc.") is not particularly
limited, the patch preparation of the present invention can be
particularly preferably used as a therapeutic drug for Attention Deficit
Disorder, a therapeutic drug for Attention Deficit Hyperactivity
Disorder, a therapeutic drug for narcolepsy and the like.

[0023] Either of methylphenidate (free form) or a salt of methylphenidate
may be present in the adhesive layer singly or as a mixture thereof. When
simply indicated as "methylphenidate" in the present specification, it
mean a free form. A free form of methylphenidate is preferable in the
present application from the aspect of skin permeability.

[0024] While the total content of methylphenidate and/or a salt thereof in
the adhesive layer and the concentration thereof in the adhesive layer
can be appropriately selected depending on the age, body weight, severity
of symptom of patients and the like. Generally, when methylphenidate
(dl-threoracemate) is used, the total content thereof in the adhesive
layer is preferably not less than 10 mg, more preferably not less than 20
mg, per a patch preparation, from the aspect of delivery of a
therapeutically effective amount of a drug. When the total content is too
high, an effect corresponding thereto is difficult to obtain. Therefore,
the upper limit is preferably not more than 300 mg, more preferably not
more than 200 mg, per a patch preparation.

[0025] When methylphenidate (dl-threoracemate) is used, the concentration
of methylphenidate and/or a salt thereof in the adhesive layer is
preferably 1-30 wt %, more preferably 5-20 wt %, per the total weight of
the adhesive layer, from the aspects of the release rate and skin
permeability of the drug. When the concentration is less than 1 wt %, a
therapeutic or prophylactic effect may not be obtained sufficiently. On
the other hand, when it is more than 30 wt %, side effects may be caused
due to a high concentration of the drug.

[0026] In the present invention, methylphenidate and the like may be
delivered to patients by adhering a single patch preparation to patients
or adhering plural patch preparations to patients. For convenient
treatment, a single patch preparation is preferably adhered.

[0027] The adhesion time is preferably at least 6 hr to deliver a
therapeutically effective amount of a drug. When the adhesion time is too
long, the amount of the drug to be delivered per unit time decreases.
Thus, it is preferably not more than 48 hr and more preferably 6-24 hr.

[0028] The site of application is not particularly limited, either, and
the patch preparation can be applied to the skin, mucous membrane (mouth
cavity, etc.) and the like. It is generally applied to the skin, for
example, arm, abdomen, back, buttock and the like.

[0029] While the therapeutically effective amount of methylphenidate
and/or a salt thereof varies depending on the age, body weight and
severity of symptoms of patients, the kind of the salt of the drug and
the like, when methylphenidate (dl-threoracemate) is used, it is, for
example, preferably 0.05-1.0 mg/kg/day, more preferably 0.075-0.3
mg/kg/day, for both children and adults. Monitoring the symptoms of the
patients after initial administration, the dose can be appropriately
controlled by adjusting the total content of methylphenidate and/or a
salt thereof in the adhesive layer (content per sheet of patch
preparation), concentration thereof in the adhesive layer,
polyisobutylene as the below-mentioned adhesive, the kind and amount of a
liquid plasticizer and the like, adhesion time and the like, so as to
afford the therapeutically effective amount.

[0030] The patch preparation of the present invention has a substantially
flat plane form. The flat shape of the patch preparation of the present
invention includes, but is not limited to, for example, about rectangle,
polygon such as triangle, pentagon and the like, or a shape defined by
about straight lines, a shape defined by curved lines such as ellipse,
circular shape and the like, a combination thereof and the like. While
the size of the patch preparation is not particularly limited, it is
preferably a size that can contain the total amount of the
above-mentioned drug. The size of the patch preparation can be
appropriately selected. For example, when the patch preparation has an
about rectangular shape, the length of one side thereof is generally
10-100 mm, and the length of other side is generally 10-80 mm.

[0031] The support to be used in the present invention is not particularly
limited and a film or sheet material known per se can be used. A material
capable of preventing a liquid plasticizer and a drug from passing
through the support and the back face of the patch preparation and
getting lost from the back face to lower the content, namely, impermeable
to these components, is preferable.

[0032] A material having such impermeability is not limited, and examples
thereof include polyester such as poly(ethylene terephthalate) and the
like, nylon such as nylon-6, nylon-66 and the like, single layer film
such as polyvinyl chloride, polyethylene, polypropylene, ethylene-vinyl
acetate copolymer, polytetrafluoroethylene, ionomer resin and the like,
metal foil, a laminate film thereof and the like.

[0033] To improve adhesiveness (anchor property) to the adhesive layer, a
laminate film of a non-porous film and a porous film, comprised of the
above-mentioned materials, may be used as a support.

[0034] A particularly preferable support is a polyester film such as
polyethylene terephthalate and the like, from the aspect of low
permeability of adhesive layer components such as methylphenidate and the
like.

[0035] The thickness of the support is preferably 10-500 μm, more
preferably 10-200 μm, in consideration of flexibility of the patch
preparation and the like. In the case of a thin patch preparation of, for
example, a plaster type or an adhesive tape type, it is preferably 10-100
μm. When the support is a laminate film of a non-porous film and a
porous film, the thickness of the non-porous film is preferably 5-200
μm, more preferably 5-100 μm, in consideration of suppression of
drug permeation and the like.

[0036] The adhesive layer formed on at least one surface of the support
contains polyisobutylene. Polyisobutylene is considered to have an effect
of stabilizing methylphenidate and a salt thereof in the adhesive layer
and an effect of promoting permeation of methylphenidate and a salt
thereof through the skin. It is preferable as an adhesive in view of the
adhesive property of the adhesive layer, safety for the skin, and the
balance of stability of methylphenidate and a salt thereof, and
preferably used as a component constituting the adhesive layer of the
patch preparation of the present invention. A single kind of
polyisobutylene may be used or a mixture of two or more kinds of
polyisobutylene having different viscosity average molecular weights may
be used. From various aspects such as suitable adhesive force and drug
solubility and the like, a mixture of two or more kinds of
polyisobutylene having different viscosity average molecular weights is
preferably used.

[0037] In the following, polyisobutylene having cohesiveness necessary for
an adhesive layer and added to an adhesive layer as an essential
component is referred to as the first polyisobutylene, and further
polyisobutylene to be added for various purposes such as increasing
adhesive force of the adhesive layer and the like is referred to as the
second polyisobutylene.

[0038] The first polyisobutylene is not particularly limited, and
polyisobutylene having a viscosity average molecular weight of
160,000-6,000,000, more preferably 1,000,000-5,000,000, most preferably
3,500,000-4,500,000, is preferable. When the viscosity average molecular
weight is less than 160,000, cohesion strength of the adhesive layer
sometimes decreases, possibly causing adhesive residue (residual adhesive
layer components on skin surface) when detaching the patch preparation.
On the other hand, when it exceeds 6,000,000, polyisobutylene becomes
less compatible with other components of the adhesive layer and fails to
maintain uniformity of the adhesive layer, again possibly causing
adhesive residue when detaching the patch preparation.

[0039] When the second polyisobutylene is added for various purposes such
as increasing adhesive force of the adhesive layer and the like,
polyisobutylene having a viscosity average molecular weight of
30,000-100,000, more preferably 40,000-80,000, most preferably
50,000-60,000, is preferably used. When it is less than 30,000, its
amount of addition may be limited, since the cohesion strength of the
adhesive layer becomes weak. When it exceeds 100,000, the molecular
weight becomes equivalent to or not very different from that of the first
polyisobutylene, which may prevent the effect of increasing the adhesive
force.

[0040] The viscosity average molecular weight in the present invention is
determined by calculating a Staudinger index (J0) according to the
Schulz-Blaschke equation with the flow time of capillary 1 of Ubbelohde
viscometer at 20° C., and with the following formula using the
obtained J0 value:

[0041] The total content (total amount when two or more kinds are used) of
polyisobutylene in the adhesive layer is preferably 20-85 wt %, more
preferably 50-85 wt %. When it is less than 20 wt %, the skin adhesion
force may be difficult to maintain during adhesion. When it is more than
85 wt %, skin irritation may be developed due to strong skin adhesion
force.

[0042] When two kinds of polyisobutylene having different viscosity
average molecular weights are to be used, the content ratio of the first
polyisobutylene and the second polyisobutylene (first
polyisobutylene:second polyisobutylene) is preferably 1:0.1-10, more
preferably 1:0.5-5, which affords suitable adhesive force and drug
solubility and the like.

[0043] The adhesive layer can contain a tackifier when desired. The
tackifier may be any appropriately selected from those known in the art
of patch and patch preparation. Examples of the tackifier include
petroleum resins (e.g., aromatic petroleum resin, aliphatic petroleum
resin and the like), terpene resin, rosin resin, coumaroneindene resin,
styrene resins (e.g., polystyrene, copolymer of styrene and
α-methylstyrene etc.), alicyclic saturated hydrocarbon resins
(preferably those having softening point (ring-and-ball method) of
50-200° C.), hydrogenated petroleum resins (e.g., alicyclic
saturated hydrocarbon resin obtained by partial hydrogenation or complete
hydrogenation of aromatic petroleum resin etc.), polybutene (e.g.,
polybutene having kinematic viscosity of 1000-10000 mm2/s at
100° C. etc.) and the like. Among these, polybutene is preferable,
since the preservation stability of methylphenidate and/or a salt thereof
becomes fine.

[0044] The tackifier may be of one kind, or two or more kinds may be
combined. When two or more kinds are to be used in combination, for
example, different kinds of resin may be combined, or the same kind of
resins having different softening points may be combined.

[0045] The content of the tackifier is preferably 15-55 wt %, more
preferably 20-50 wt %. When the content of the tackifier is less than 15
wt %, the tackiness (adhesiveness) and cohesion strength of the adhesive
layer sometimes become poor. When it exceeds 55 wt %, the adhesive layer
becomes hard and tends to is show lower skin adhesiveness.

[0046] A liquid plasticizer contained in the adhesive layer can soften the
adhesive layer and decrease skin irritation during adhesion and/or
detachment of a patch preparation.

[0047] As the liquid plasticizer, a plasticizer which is liquid at ambient
temperature, shows plasticizing action on an adhesive layer, and
compatible with the aforementioned polyisobutylene contained in the
adhesive layer can be preferably used. In addition, for example, a
plasticizer having an ester group in the structural formula, and a
plasticizer that improves transdermal absorbability and preservation
stability of methylphenidate and/or a salt thereof are preferable.

[0048] Specific examples thereof include fatty acid esters such as fatty
acid ester made of a higher fatty acid having a carbon number of 12 to 16
and a lower monovalent alcohol having a carbon number of 1 to 4 and the
like; fatty acid having a carbon number of 8 to 10; higher alcohol
(preferably higher alcohol having a carbon number of 10 to 30); fats and
oils and the like. A liquid plasticizer from among these, which is liquid
at ambient temperature, can be used. Specific examples of the liquid
plasticizer include squalene and lanolin. In the present specification,
being liquid at ambient temperature means showing flowability at
20° C.

[0049] Examples of the aforementioned fats and oils include olive oil,
castor oil and the like. Preferable examples of the aforementioned fatty
acid ester made of a higher fatty acid having a carbon number of 12 to 16
and a lower monovalent alcohol having a carbon number of 1 to 4 include
isopropyl palmitate, isopropyl myristate, ethyl laurate and the like.
Examples of other preferable fatty acid ester include isotridecyl
myristate, ethyl oleate, diisopropyl adipate, octyl palmitate and the
like. Preferable examples of the higher alcohol include
2-octyl-1-dodecanol (octyldodecanol).

[0050] A liquid plasticizer may be used singly, or may be used in a
combination of two or more kinds thereof. The amount of the liquid
plasticizer is preferably 5-30 wt %, more preferably 10-20 wt %. When the
amount is less than 5 wt %, the adhesive layer may insufficiently be
plasticized and skin irritation sometimes may not be decreased. When it
exceeds 30 wt %, the liquid plasticizer sometimes cannot be maintained in
the adhesive layer even with the cohesion strength of the adhesive
(polyisobutylene). As a result, the liquid plasticizer blooms on the
adhesive layer surface and the adhesiveness of the patch preparation to
the skin may become inferior.

[0051] The liquid plasticizer preferably has an HLB value showing
hydrophile-lipophile balance of 1.0-3.3. The HLB value ranges from 0 to
20, and a value closer to 0 has a higher lipophilicity and a value closer
to 20 has a higher hydrophilicity.

[0052] Using a liquid plasticizer having an HLB value of not more than
3.3, the stability of methylphenidate and/or a salt thereof in the patch
preparation can be further improved. Since the HLB value of the liquid
plasticizer is not less than 1.0, the compatibility of methylphenidate
and/or a salt thereof with the adhesive layer can be enhanced, and the
possibility of blooming of methylphenidate and/or a salt thereof on the
adhesive layer surface can be decreased. The HLB value is more preferably
1.0-2.6.

[0054] The HLB value in the present specification is a value calculated
according to the following formula by Oda, Teramura et al.

HLB value=[(Σinorganic value)/(Σorganic value)]×10

[0055] Here, the (Σinorganic value) and (Σorganic value) are
obtained by respectively adding inorganic values and organic values of
the constituent units of molecule of the liquid plasticizer, and the
inorganic values and organic values are obtained from the organic concept
proposed by Atsushi Fujita (see, for example, Atsushi Fujita, "Chemical
Region", Vol. 11, No. 10 (1957), 719-725 etc.). More specifically, the
inorganic value is determined by a functional group and, for example,
--OH is 100, --COOH is 150, --NH2 (amine) is 70, --COOR (ester
group) is 60, --O-- is 20, --CO-- is 65, aromatic ring (monocycle) is 15,
and nonaromatic ring (monocycle) is 10. The organic value is a carbon
number of a molecule multiplied by 20. For example, the value for a group
having a branched aliphatic group such as isopropyl group is calculated
by subtracting 10 from this value, and the like. The detail of the
calculation method is also described in the following document and the
like besides the above-mentioned document.

[0057] % A release liner to protect the adhesive surface can be laminated
on the adhesive surface of the adhesive layer of the patch preparation,
before applying the patch preparation to the skin. The release liner is
not particularly limited, and examples of the material thereof include
those known per se in the field. Specific examples thereof include
plastic films of polyesters such as poly(ethylene terephthalate),
poly(vinyl chloride), poly(vinylidene chloride), various acrylic-based
and methacrylic-based polymers, polystyrene, polycarbonate, polyimide,
acetyl cellulose, regenerated cellulose (cellophane), celluloid and the
like, high-quality paper, glassine paper and the like and a laminate film
with polyolefin films and the like. For safety, economic efficiency and
drug-transfer properties, a polyester film is preferably used.

[0058] The release liner is preferably treated for easy peeling on the
interfacial surface side with an adhesive, so as to facilitate peeling
from the adhesive layer. While the easy peeling treatment is not limited,
a known method can be applied. For example, a treatment for forming a
peeling-treated layer using a release agent comprising a curable silicone
resin as a main component by a coating method such as bar coating,
gravure coating and the like can be applied. The thickness of the
peeling-treated layer is preferably 0.01-5 μm in view of ensured
release property and uniformity of coated film.

[0059] The thickness of the release liner is preferably about 25-100
μm, more preferably about 40-80 μm, so as to maintain the shape of
a flexible patch preparation, facilitate holding of a patch preparation
and the like.

[0060] While the production method of the patch preparation of the present
invention mentioned above is not limited, it can be produced, for
example, by mixing methylphenidate and/or a salt thereof,
polyisobutylene, and components such as a liquid plasticizer, and when
desired, a tackifier and the like with a solvent, applying the obtained
solution or dispersion to a support, drying same to give a sheet for
production of a patch preparation, and cutting the sheet. The
aforementioned coating can be performed by, for example, casting,
printing or a technique known per se in the art.

[0061] While the solvent is not limited, one having compatibility with the
aforementioned respective components constituting the adhesive layer,
easily volatilizable during a drying process and not impairing the effect
of the invention is preferable. Examples of the solvent include aromatic
hydrocarbons such as toluene, xylene and the like, aliphatic hydrocarbons
such as hexane and the like, esters such as ethyl acetate and the like,
alcohols such as ethanol and the like, ethers such as diethyl ether,
tetrahydrofuran, etc. and the like. These may be used alone or in a
mixture of two or more kinds thereof in combination.

[0062] The aforementioned drying may be performed by air-drying, or
according to a known method using a dryer, hot air, far-infrared
radiation and the like.

[0063] While the method of mixing the aforementioned respective components
is not limited, examples thereof include kneading machines such as a
kneader, a planetary mixer and the like, dispersion machines such as
homogenizer and the like, stirring machines such as propeller-type blade
stirring machine, etc. and the like. These can be used alone or in a
combination of two or more kinds thereof.

[0064] The method of the aforementioned cutting is not limited and any
known cutting method such as laser, straw cutter and the like can be
used.

EXAMPLES

[0065] The present invention is explained in detail in the following by
referring to Examples and Comparative Examples, which are not to be
construed as limitative. In the following, the parts mean parts by
weight.

[0070] Using adhesive composition A (3.3 g) and toluene (6.3 mL) as a
solvent and according to the blending ratios shown in Table 1, viscous
toluene solutions of adhesive composition were prepared, and the obtained
solutions were applied to a polyethylene terephthalate (PET) release
liner (thickness 75 μm) subjected to a silicone release treatment,
such that the thickness of the adhesive layer after drying was 100 μm,
and dried in a hot-air circulation type dryer at 80° C. for 10 min
to form an adhesive layer. The adhesive surface of the adhesive layer was
adhered to a 25 μm-thick polyethylene terephthalate (PET) support to
give a sheet for production of a patch preparation. This was cut with a
straw cutter to give a patch preparation sheet (100 mm×400 mm). One
patch preparation contained about 40 mg of methylphenidate.

Comparative Example 1

[0071] In the same manner as in Examples 1-4 except that a viscous ethyl
acetate solution of an adhesive composition was prepared using adhesive
composition B and according to the blending ratio shown in Table 1, and
an aging treatment at 60° C. was performed for 48 hr after drying
in a hot-air circulation type dryer, a patch preparation sheet was
obtained.

Comparative Example 2

[0072] In the same manner as in Examples 1-4 except that a viscous ethyl
acetate solution of an adhesive composition was prepared using adhesive
composition C and according to the blending ratio shown in Table 1, and
an aging treatment at 60° C. was performed for 48 hr after drying
in a hot-air circulation type dryer, a patch preparation sheet was
obtained. Note that AL-A (aluminum acetylacetonate) is a crosslinking
agent.

Comparative Example 3

[0073] In the same manner as in Examples 1-4 except that a viscous ethyl
acetate solution of an adhesive composition was prepared using adhesive
composition D and according to the blending ratio shown in Table 1, and
an aging treatment at 60° C. was performed for 48 hr after drying
in a hot-air circulation type dryer, a patch preparation sheet was
obtained. Note that AL-A (aluminum acetylacetonate) is a crosslinking
agent.

[0074] The patch preparations obtained in Example 1 and Comparative
Examples 1-3 were preserved under the preservation conditions at
60° C. for 2 weeks, methylphenidate in a plaster (adhesive layer)
was quantified by HPLC before the start of preservation and after 2
weeks' preservation, and the ratio of methylphenidate remaining after the
preservation was obtained. The HPLC conditions were as follows. For each
of Example 1 and Comparative Examples 1-3, methylphenidate was quantified
at 3 points of the plaster (adhesive layer) before the start of
preservation and after 2 weeks' preservation, the ratio of
methylphenidate remaining at 3 points was obtained from the
quantification values, and the average value and standard deviation
thereof were determined. The ratio of remaining methylphenidate is
expressed as percentages (wt %) of methylphenidate after 2 weeks'
preservation relative to that before the start of preservation. The
average value and standard deviation thereof are shown in Table 2.

[0076] As is clear from Table 2, methylphenidate content did not decrease
even under harsh preservation conditions at 60° C. in Example 1.
However, the content decreased in Comparative Examples 1-3 and,
particularly in Comparative Example 2, the ratio (average value) of
residual methylphenidate was 11.6 wt %, showing a remarkable decrease in
the content.

Experimental Example 2

Human Skin Permeability Test

[0077] Using the patch preparations obtained in Example 1 and Comparative
Examples 1-3, human skin permeability test was performed. In the test, a
patch preparation (cut into 6 mm φ circle) was adhered to the surface
of a stratum corneum layer of the isolated human skin (cut into 16
mmφ circle, thickness 20 μm), set in a glass diffusion cell (e.g.,
Franz cell available from Keystone Scientific K.K. and the like), such
that the dermis layer side of the skin came into contact with a receptor
solution, sampling the receptor solution at given time intervals, and
quantifying methylphenidate in the receptor solution by HPLC. Saline at
32° C. was used as a receptor solution. The HPLC conditions were
the same as in Experimental Example 1, except the detection wavelength at
257 nm.

[0078] The test was performed 5 times for each of the patch preparations
obtained in Example 1 and Comparative Examples 1-3. The permeation rate
of methylphenidate through the skin as determined from the quantified
value is shown in FIG. 1, cumulative permeation amount of methylphenidate
through the skin is shown in FIG. 2, and permeability evaluation
parameters are shown in Table 3. In the Table, each plot shows an average
value of 5 tests and the bar shows standard deviation.

[0079] As is clear from Table 3, FIG. 1 and FIG. 2, the permeation rate
and cumulative permeation amount of methylphenidate through the skin were
high in Example 1, and methylphenidate availability was 66.4 wt %. In
contrast, the permeation rate and cumulative permeation amount of
methylphenidate through the skin were low in Comparative Examples 1-3,
and methylphenidate availability was not more than 40 wt %.

Experimental Example 3

Stability Testing of the Drug Content

[0080] The patch preparations obtained in Examples 1-4 were subjected to a
test in the same manner as in Experimental Example 1. The ratio of
methylphenidate remaining after preservation was determined, and the
average value and standard deviation shown in Table 4 were obtained.

[0081] As is clear from Table 4, the methylphenidate content did not
decrease even under harsh preservation conditions at 60° C. in
Example 1. However, the content decreased in Examples 3 and 4 and,
particularly in Example 3, the ratio (average value) of residual
methylphenidate was 15.2 wt %, showing a remarkable decrease in the
content.

INDUSTRIAL APPLICABILITY

[0082] Since the patch preparation of the present invention shows superior
skin permeability, and is superior in methylphenidate availability, it
can be preferably used for the treatment of Attention Deficit Disorder,
Attention Deficit Hyperactivity Disorder and the like. Particularly, it
is effective for treating children suffering from the aforementioned
disorders through children's school hours and in a comparatively short
time.

BRIEF DESCRIPTION OF THE DRAWINGS

[0083] FIG. 1 is a graph showing time-course changes of permeation rate of
methylphenidate through the skin in Experimental Example 2.

[0084] FIG. 2 is a graph showing time-course changes of cumulative
permeation amount of methylphenidate through the skin in Experimental
Example 2.